Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy

利用嘧啶核苷酸合成依赖性进行 IDH 突变胶质瘤治疗

基本信息

批准号：
10180738
负责人：
Kalil G Abdullah
金额：
$ 37.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-07 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180738
关键词：
Achievement Address Adult Glioma Anabolism Apoptosis Biological Biological Markers Brain Brain Neoplasms Branched-Chain Amino Acids Catabolism Cell Death Cell Survival Cells Central Nervous System Neoplasms Chemicals Chromatin Structure Clinic Clinical Clinical Trials Coupled DHODH gene DNA biosynthesis Defect Dependence Dihydroorotate dehydrogenase Disease Disease model Drug Targeting Endoplasmic Reticulum Enzyme Inhibitor Drugs Enzymes FDA approved Foundations Functional disorder Future Gene Expression Gene Silencing Genes Genetic Genetic Heterogeneity Glioblastoma Glioma Glutaminase Glutamine Goals Homeostasis Human Hypersensitivity Impairment Individual Isocitrate Dehydrogenase Lipids Malignant - descriptor Malignant Neoplasms Medical Metabolic Metabolic Pathway Metabolism Modeling Molecular Mutate Mutation Newly Diagnosed Oncoproteins Organoids Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phospholipids Pre-Clinical Model Predisposition Primary Brain Neoplasms Production Protein Glycosylation Proteins Pyrimidine Pyrimidine Nucleotides Pyrimidine Synthesis Inhibition RNA chemical synthesis Radiation therapy Research Resistance Role Stress Surveys Survival Rate System Testing Therapeutic Tissues Translating Tumor Cell Line United States Work cancer therapy clinical translation combat design endoplasmic reticulum stress experimental study gain of function glioma cell line in vivo inhibitor/antagonist mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics nucleotide metabolism patient derived xenograft model pre-clinical preclinical trial predicting response predictive marker research clinical testing response standard care success treatment response treatment strategy tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for new ways to combat this disease, the standard treatment for gliomas has not changed since 2005 and no new glioma medical therapies have been approved in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in a gene called IDH1. IDH1 mutations are present in 70-90% of lower grade gliomas and secondary glioblastomas, a highly aggressive subtype of glioma. We surveyed hundreds of drugs and discovered that a class of drugs that inhibit a particular metabolic pathway preferentially killed brain tumor cells with IDH1 mutations. Our proposal builds on this discovery by addressing three Specific Aims. Specific Aim #1 is to understand the molecular mechanisms through which IDH1 mutations increase sensitivity to inhibitors of this metabolic pathway. We will use cultured brain tumor cell lines that harbor or lack IDH1 mutations to test our hypothesis that the combined effects of IDH1 mutations and these inhibitors severely impair protein processing and lipid production in tumor cells, creating stress that ultimately triggers cell death. Specific Aim #2 is to use organoid models derived from human glioma tissue to assess whether the presence of an IDH1 mutation successfully predicts response to inhibitors of the metabolic pathway we propose targeting. Organoids represent powerful preclinical disease models because they allow us to test new therapeutic strategies in a cellular system that accurately reflects the makeup of human brain tumors. Specific Aim #3 is to use a mouse model of glioma to assess whether inhibiting the metabolic pathway we've identified to be important for IDH1 mutant brain tumor cells leads to desirable therapeutic responses, including a block in tumor growth and extension of host survival. These studies will clarify whether targeting this pathway is likely to provide benefit for human patients with IDH1 mutated brain tumors. Taken together, our work will outline and test a new treatment strategy for brain tumor patients that could be rapidly translated to the clinic if our studies are successful. Furthermore, our efforts may demonstrate that IDH1 mutations can be used to faithfully identify individuals whose tumors are poised to respond to the treatment strategy we are developing, thereby providing a way to design potential future clinical trials that have the greatest chance to provide benefit for glioma patients.

项目摘要胶质瘤代表26,000例新诊断的恶性脑和中枢神经系统中的80％每年在美国，肿瘤是最致命和治疗的人类癌症之一。尽管迫切需要新的方法来打击这种疾病，但胶质瘤的标准治疗方法尚未自2005年以来发生了变化，在过去十年中，没有批准新的神经胶质瘤医疗疗法。作为回应在这一挑战中，我们设计了一种新的方法来治疗在一个名为IDH1基因中具有突变的神经膜瘤。 IDH1 突变存在于70-90％的低级神经胶质瘤和二级胶质母细胞瘤中，这是一种高度侵略性的神经胶质瘤的亚型。我们调查了数百种药物，发现一类抑制特定的药物代谢途径优先杀死具有IDH1突变的脑肿瘤细胞。我们的提议以此为基础通过解决三个具体目标来发现。特定目的＃1是了解分子机制 IDH1突变会增加对该代谢途径抑制剂的敏感性。我们将使用文化脑肿瘤细胞系藏有或缺乏IDH1突变以检验我们的假设，即IDH1的综合作用突变，这些抑制剂严重损害了肿瘤细胞中的蛋白质加工和脂质的产生，从而产生强调最终会触发细胞死亡。特定目的＃2是使用源自人神经胶质瘤的器官模型组织以评估IDH1突变的存在是否成功预测了对抑制剂的反应代谢途径我们提出靶向。器官代表强大的临床前疾病模型，因为它们允许我们在细胞系统中测试新的治疗策略，以准确反映人类的构成脑肿瘤。特定目的＃3是使用胶质瘤的小鼠模型来评估是否抑制代谢我们已经确定对IDH1突变脑肿瘤细胞很重要的途径导致理想的治疗反应，包括肿瘤生长的块和宿主存活的扩展。这些研究将阐明是否靶向这一途径可能会为患有IDH1突变脑肿瘤的人类患者提供益处。拍摄一起，我们的工作将概述和测试可能迅速的脑肿瘤患者的新治疗策略如果我们的研究成功，可以翻译成诊所。此外，我们的努力可能表明IDH1 突变可用于忠实地识别肿瘤准备应对治疗的个体我们正在制定的策略，从而提供了一种方法来设计具有最大最大临床试验的潜在临床试验有机会为神经胶质瘤患者提供好处。